Abstract Prosthetic joint infection (PJI) is the bane of elective total joint replacement (TJR) surgery, of which the vast majority is caused by Staphylococcal species. Although the number of primary infections following TJR is low (1-5%), reinfection rates are very high (15-40%), which has led to the orthopaedic paradigm that S. aureus infection of bone is incurable. Additionally, PJI is known to be a non-random event that is largely determine by patient-specific factors, as infections are caused by only a few prevalent nosocomial strains (i.e. MRSA USA300), and implementation of the most rigorous surgical systems is incapable of reducing infection rates below 1%. Moreover, ~13% of patients infected with S. aureus become septic and die from multiorgan failure, while others recover with little intervention. To address these very significant issues, we propose the Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI), which is the evolution of two highly successful programs (AOTrauma Clinical Priority Program on Bone Infection (AO-CPP); and NIAMS P50 CORT AR54041 ?Translating Molecular Signal Pathways to Orthopaedic Trauma Care?) that will be completed this year. To capitalize on the salient strengths of these programs, the CoRTOBI now proposes to advance and translate the major discoveries from the AO-CPP on S. aureus infection of bone and host immunity, using the proven administrative structure of the P50 CORT. These discoveries include: 1) S. aureus colonization of the osteocytic-canalicular network of live bone, 2) novel antibiotics that specifically target these mechanisms, which can be 3D-printed into custom spacers, 3) development of a custom multiplex Luminex assay to elucidate the immune proteome of S. aureus, and 4) identification of the anti-Isd vs. anti-Atl immune proteome ratio as a susceptible vs. protective index of host immunity against S. aureus. The proposed CoRTOBI will consist of an Administrative Core that will provide operational and fiscal management of the CoRTOBI, as well as a Clinical Research Sub-Core, a Biostatistics Sub-Core, an Enrichment Programs, and a Pilot and Feasibility Project Program. There are two Research Projects. Project 1 is focused on elucidating the mechanisms of S. aureus motility in bone and developing novel antibiotic impregnated 3D-printed spacers. Project 2 is focused on defining the susceptible vs. protective immune proteomes of Staphylococcus osteomyelitis and interventions for septic death. The Projects will be supported by an Osteoimmunology Research Core, which will provide state of the art imaging, biomaterial fabrication and immunoassay analyses. At the conclusion of this CoRTOBI we will have new knowledge on the microbial pathogenesis of bone infection and the host response. We will also develop novel diagnostics and interventions for patients with osteomyelitis.